Depression is a known risk factor for morbidity and mortality in a wide range of diseases, including HIV/AIDS. Because the prevalence of depression in HIV seropositive individuals is double that of the general population, effectively targeting depression in people living with HIV is an important public health need. Moreover, because depression and HIV infection share certain alterations in immune system function, namely suppressed innate immunity and overactivated cellular immunity marked by systemic inflammation, it may be possible to improve immune function in patients with HIV/AIDS by treating their depression. Although many clinicians generally consider selective serotonin reuptake inhibitors (SSRIs) safe and effective in treating depression in HIV/AIDS, there have been very few randomized controlled trials (RCTs) of antidepressant medications among depressed HIV seropositive individuals, and results have been mixed. Moreover, no previous trials examined biomarkers of immune dysregulation common to both depression and HIV/AIDS. Our prior work has established links between depression, immune dysregulation, and HIV disease progression on the one hand, and immune regulating and antiviral effects of SSRI treatment on the other. For example, we found depression was associated with decreased natural killer (NK) cytolytic activity in both medically healthy individuals and in HIV- infected patients, and we showed that depression was associated with accelerated HIV disease progression. We also observed that resolution of depression was associated with increased NK cytotoxicity and we demonstrated that ex vivo SSRI treatment of immune cells enhances NK cytolytic activity. Further, we discovered that an SSRI inhibited HIV infectivity of immune cells e vivo, and that SSRI treatment significantly down-regulated the expression of HIV receptors and co-receptors (CD4, CXCR4, CXCR5) on macrophages and T-cells. Our studies thus indicate that SSRIs may have a direct action on peripheral immune cells. Taken together, this work suggests that SSRI treatment could conceivably reduce psychiatric morbidity and help reverse immune dysregulation in depressed, People Living with HIV/AIDS (PLWH). To pursue our long-term objective of successfully treating co-morbid mental and medical disorders in HIV/AIDS, this study aims to determine whether: 1) SSRI treatment significantly increases innate immunity and decreases chronic inflammation and immune activation, and 2) changes in depressive symptoms correlate with changes in immune regulation in HIV/AIDS. This study will be the first double-blind, placebo controlled trial of a SSRI for treating depression in HIV/AIDS with a focus on innate immunity and inflammation. If successful, this project will advance the field of HIV care by demonstrating for the first time, immune benefits of drug therapy for clinical depression and resolution of depressive symptoms among people with well-controlled viral load: thus leading to a potential new use of SSRIs as adjuncts to cART, which could lead to a change in clinical care of depressed PLWH, and set the stage for SSRI immune studies in non-depressed PLWH.